Ataxin-1 is one of a group of polypeptides implicated in spinocerebrellar ataxia (SCA) conditions, also called autosomal dominant cerebellar ataxias (ADCAs). SCA disorders are heritable autosomal dominant neurodegenerative conditions commonly featuring progressive ataxia, which is irregularity of muscle action due to failure of muscle coordination. Examples of other symptoms typically shown by patients diagnosed with SCA are paralysis of the ocular muscles (ophthalmoplegia) and loss of articulation of speech (dysarthria), as associated with SCA2 and SCA7; degeneration and loss of types of brain cells, as in loss of cerebellar Purkinje cells in SCA1 for example; and dementia, as associated with SCA2 and SCA6.
Several of the SCA disorders are characterized by genetic anticipation, which is the tendency of certain diseases to appear at earlier onset ages and/or with increased severity in each successive generation. In many cases, genetic anticipation has been shown to have a biological basis in the expansion in length of a stretch of triplet repeats that encode a particular amino acid. SCA1 shows genetic anticipation and is associated with expansions in the size of a polyglutamine tract in ataxin-1 polypeptide encoded by repeated CAG codons (Matilla et al., 1993, Presymptomatic analysis of spinocerebellar ataxia type 1 (SCA1) via the expansion of the SCA1 CAG-repeat in a large pedigree displaying anticipation and parental male bias, Hum Molec Genet 2: 2123–2128). Genetic anticipation has also been observed in families afflicted with several other of the SCA disorders such as SCA2, SCA3, SCA5, SCA6, SCA7, SCA8, SCA10, and in addition to the ataxin-1 gene of SCA1, expansions of CAG repeats have been found in alleles of those SCA genes that have been characterized to date: the SCA2/ataxin-2, SCA3/MJD1, SCA6/CACNA1A, and SCA7/ataxin-7 genes. Therefore, all of the SCA genes that have been studied at the molecular level indicate that expansions of CAG repeats are correlated with the genetic anticipation observed in the corresponding SCA disorder. While family history evidence has also been presented for genetic anticipation in SCA4 (Flanigan et al., 1996, Am J Hum Genet 59: 392–399), the SCA4 gene has not yet been identified and characterized.
Ataxin-1, -2, and -7, ataxin-3/MJD1, and CACNA1A polypeptides are detected in the cytoplasm of many types of neural cells, with the levels of expression varying from cell type to cell type, and with overlapping but non-identical patterns of expression displayed by these different polypeptides. The formation of nuclear inclusion bodies immunoreactive for these SCA-related polypeptides is positively correlated with the length of the polyglutamine tracts in the polypeptides. Interactions of these polypeptides with several different types of binding partners have been reported, and these interactions are believed to contribute in different ways to development of the SCA disease condition. For example, ataxin-1 polypeptide has been found to associate with cerebellar leucine-rich acidic nuclear protein (LANP) in the nuclear matrix of Purkinje cells, the primary site of the pathological effects of SCA1 (Matilla et al., 1997, Nature 389: 974–978). Association with nuclear proteins is thought to alter the conformation of ataxin-3/MJD1 polypeptide, exposing the polyglutamine tract (Perez et al., 1999, Hum Mol Genet 8: 2377–2385). Certain SCA-related polypeptides have been reported to have RNA-binding activity, either as part of the SCA-related polypeptide itself, or by binding to a polypeptide with RNA-binding activity. For example, ataxin-1 polypeptide binds RNA in vitro, with the RNA-binding capability inversely proportional to the length of the polyglutamine tract (Yue et al., 2001, Hum Mol Genet 10: 25–30), and ataxin-2 interacts with ataxin-2 binding protein 1 (A2BP1), a polypeptide containing RNA-binding motifs (Shibata et al., 2000, Hum Mol Genet 9: 1303–1313). Interestingly, in cells containing ataxin-1 with an expanded glutamine tract, down-regulation of particular neuronal genes is postulated to be an early step in SCA1 pathogenesis (Lin et al., 2000, Nat Neurosci 3: 157–163). In addition, there is evidence that polyglutamine tracts tend to self-associate, sequestering polypeptides containing them in nuclear inclusions and possibly trapping other polypeptides required for cell viability, such as CREB-binding protein (CBP) (McCampbell et al., 2000, Hum Mol Genet 9: 2197–2202). One possible outcome of expression of polyglutamine-containing polypeptides in neural cells is cell death through a non-apoptotic mechanism (Evert et al., 1999, Hum Mol Genet 8: 1169–1176).
In order to develop more effective treatments for spinocerebellar conditions and diseases, such as SCA1 and SCA4, information is needed about previously unidentified or uncharacterized SCA-related polypeptides.